In this renewal application, research is proposed to elucidate the toxicologic mechanism(s) for the liver carcinogenicity of certain peroxisome-proliferating agents (PPA). The dominant hypotherical mechanism, for which there is substantial supporting evidence, is that these agents increase cellular levels of H2O2 leading to macromolecular damage and cellular alteration. During the previous grant period, we were unable to obtain direct confirmation for this sequence, but further experiments are proposed to examine the hypothesis in a rigorous manner. Findings in the preceding research also lead us to consider additional mechanisms, which may operate independent of oxidative damage or in conjunction with it. The specific aims for the contimued research are as follows: (1) Identify two genetically-defined groups of mice and a PPA most likely to show differences in PPA-induced tumorigenesis, assuming the H2O2 hypothesis to be true and delineate the dose-response effects of that PPA on tumorigenesis in those two groups; (2) Investigate PPA-induced oxidative damage on liver cell macromolecules and; (3) Investigate PPA-induced liver cell proliferation as a mechanistically important event in PPA carcinogenicity.